The term avermectin (previously referred to as C 076) is used to describe a series of compounds isolated from the fermentation broth of an avermectin producing strain of Streptomyces avermitilis and derivatives thereof. The morphological characteristics of the culture are completely described in U.S. Pat. No. 4,310,519. The avermectin compounds are a series of macrolides, each of which is substituted thereon at the 13 position with a 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group. The avermectin compounds and the instant derivatives thereof have a very high degree of anthelmintic and anti-parasitic activity.
Also included in the prior art are certain synthetically modified avermectins such as 22,23-dihydro avermectin B1a/B1b also known as ivermectin disclosed in U.S. Pat. No. 4,199,569.
The avermectin series of compounds, which are isolated from a fermentation broth, have the following structure:
wherein R is the 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group of the structure: ##STR1## wherein R is the 4'(.alpha.-L-oleandrosyl)-.alpha.-L oleandrose group of the structure: ##STR2## and wherein the broken line indicates a single or a double bond; R.sub.1 is hydroxy and is present only when said broken line indicates a single bond; PA1 R.sub.2 is iso-propyl or sec-butyl; and PA1 R.sub.3 is methoxy or hydroxy.
There are eight different major avermectin natural product compounds and they are given the designations A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b based upon the structure of the individual compounds.
In the foregoing structural formula, the individual avermectin compounds are as set forth below. (The R group is 4'(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose):
______________________________________ R.sub.1 R.sub.2 R.sub.3 ______________________________________ A1a (22,23-Double Bond) sec-butyl --OCH.sub.3 A1b (22,23-Double Bond) iso-propyl --OCH.sub.3 A2a --OH sec-butyl --OCH.sub.3 A2b --OH iso-propyl --OCH.sub.3 B1a (22,23-Double Bond) sec-butyl --OH B1b (22,23-Double Bond) iso-propyl --OH B2a --OH sec-butyl --OH B2b --OH iso-propyl --OH ______________________________________
The avermectin compounds are generally isolated as mixtures of a and b components. Such compounds differ only in the nature of the R.sub.2 substituent and the minor structural differences have been found to have very little effect on the isolation procedures, chemical reactivity and biological activity of such compounds.
The 13-deoxy avermectin aglycone compounds, which lack the 13-disaccharide group are also starting materials for the instant compounds. They are disclosed in U.S. Pat. Nos. Re. 32,006 and 32,034.
The avermectin B1 and 22.23 dihydro avermectin B1 compounds are of superior activity and mixtures of the a and b compounds have been selected to be marketed for their broad spectrum antiparasitic activity against both animal and plant parasites. The avermectin A2 and B2 compounds are of a considerably lower level of activity and are not marketed products. However, the conversion of the A2 and B2 compounds to the 23-deoxy-.DELTA.23,24-avermectin compounds produces compounds of significantly higher levels of activity. Thus, the A2 and B2 compounds, which would normally be discarded in the preparation of the B1 and 22,23-dihydro B1 compounds, are utilized in the preparation of compounds with levels of activity commensurate with marketed products.